title: Specific JNK inhibition by D-JNKI1 protects Purkinje cells from cell death in Lurcher mutant mouse.
abstract: In the Lurcher mutant mouse (+/Lc), Purkinje cells (PCs) selectively die due to the mutation that converts alanine to threonine in the glutamate ionotropic receptor GRID 2, thus resulting in a constitutively leaky cation channel. This intrinsic cell death determines a target-dependent cell death of granule cells and olivary neurons and cerebellum cytoarchitecture is severely disrupted in the adult Lurcher mutant. Although the +/Lc mutant has been widely characterized, less is known about the molecules involved in +/Lc PC death. We, here, used organotypic cerebellar slice cultures from P0 mice to investigate the role of c-jun N-terminal kinase (JNK) in +/Lc PC death by using D-JNKI1 as very specific tool to inhibit its action. Our results showed that D-JNKI1 treatment increased the number of +/Lc PC at 14 DIV of 3.6-fold. Conversely, this specific JNK inhibitor cell permeable peptide did not increase PC number in +/+ treated versus untreated cultures. These results clearly indicate that JNK plays an important role in +/Lc PC mechanism of cell death.
authors.affiliation: Centre National de la Recherche Scientifique, UMR7102-Neurobiologie des Processus Adaptatifs, Paris, France.
authors.forename: Mariaelena
authors.initials: M
authors.lastname: Repici
authors.forename: Hadi S
authors.initials: HS
authors.lastname: Zanjani
authors.forename: Vanessa
authors.initials: V
authors.lastname: Gautheron
authors.forename: Tiziana
authors.initials: T
authors.lastname: Borsello
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dusart
authors.forename: Jean
authors.initials: J
authors.lastname: Mariani
mesh_terms: D000409:Alanine / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death; D002463:Cell Membrane Permeability; D002531:Cerebellum / Q000166:cytology* / Q000473:pathology; D003433:Crosses, Genetic; D005260:Female; D005838:Genotype; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants / Q000502:physiology*; D009154:Mutation; D009474:Neurons / Q000201:enzymology / Q000502:physiology; D010455:Peptides / Q000502:physiology*; D011689:Purkinje Cells / Q000166:cytology; D017470:Receptors, Glutamate / Q000235:genetics*; D013912:Threonine / Q000235:genetics
chemical_list: D010455:Peptides; D017470:Receptors, Glutamate; C107913:glutamate receptor delta 2; D013912:Threonine; D048670:MAP Kinase Kinase 4; C478085:D-JNKI-1; D000409:Alanine